CD27 is a member of the tumor necrosis factor receptor (TNFR) super family which also includes TNFR type I and II (CD120a and b), nerve growth factor receptor (NGFR), CD30 (associated with Hodgkin's lymphoma), Fas/Apo-1 (CD95), CD40, 4-1 BB and OX40. These proteins are known to play a very important role in cell growth and differentiation as well as apoptosis or programmed cell death (Smith, C. A. et al. (1994) Cell 76:959-962). Homology among these family members is restricted to the extracellular region and is characterized by the presence of a cysteine knot motif which occurs three times in CD27 (McDonald, N. Q. and Hendrickson, W. A. (1993) Cell 73:421-424).
CD27 is a glycosylated, type I transmembrane protein of about 55 kd and exists as homodimers with a disulfide bridge linking the two monomers. The disulfide bridge is in the extracellular domain close to the membrane (Camerini, D. et al. (1991) J. Immuuol. 147:3165-3169; Gravestein, L. A. et al. (1993) Eur. J. Immunol. 23:943-950). The ligand for CD27, CD70, belongs to the TNF family of ligands. CD70 is a type II transmembrane protein with an apparent molecular weight of 50 kd (Goodwin R. G. et al. (1993) Cell 73:447-456; Bowman, M. R. et al. (1994) J. Immunol. 152:1756-1761). Based on homology to TNF.alpha. and TNF.beta., especially in the .beta. strands C, D, H and I, CD70 is predicted to have a trimeric structure made up of three identical subunits which possibly interact with three CD27 homodimers (Peitsch, M. C. and Tschopp, J. (1995) Mol. Immunol. 32:761-772). TNF.alpha., which is also a type II transmembrane protein, is released from the cell by proteolytic cleavage, whereas TNF.beta. and NGF are secreted. So far there are no reports as to the existence of a naturally-occurring soluble form of CD70.
Expression of both CD27 and its ligand CD70 is restricted to discrete populations of both T and B cells. Although CD27 is expressed on the surface of resting T cells, CD70 appears only on activated T and B cells (Sugita, K. et al. (1992) J. Immunol. 149:3208-3216; Hintzen, R. Q. et al. (1993) J. Immunol. 151:2426-2435; Agematsu, K. et al. (1994) J. Immunol. 153:1421-1429; Hintzen, R. Q. et al. (1995) J. Immunol. 154:2612-2623). Within the T cell subsets, CD27 is stably expressed on the CD45RA.sup.+ population of T cells even after activation, whereas on CD45RO.sup.+ cells, it is weakly expressed and lost after activation (Sugita, K. et al. (1992) J. Immunol. 149:3208-3216; Hintzen, R. Q. et al. (1993) J. Immunol. 151:2426-2435). On CD45RA.sup.+ cells, activation by various means results in the up-regulation of CD27 expression (Hintzen, R. Q. et al. (1993) J. Imminol. 151:2426-2435; Maurer, D. et al. (1990) Eur. J. Immunol. 20:2679-2684). Although CD70 is not detectable on either CD45RA.sup.+ or CD45RO.sup.+ resting T cells, activation through the TcR/CD3 complex results in the expression of CD70 predominantly on CD45RO.sup.+ T cells. The reciprocal expression of CD27 and CD70 on subsets of helper cells suggested an important role for the molecules in T-T interactions, T cell activation, and regulation of immunoglobulin synthesis. Significant amounts of CD27 can also be detected on a subpopulation of B cells present in peripheral blood and tonsils (Maurer, R. Q. et al. (1995) J. Immunol. 154:2612-2623), and the expression can be enhanced after activation with PMA/ionomycin. CD27 is also expressed on the CD3-bright thymocytes and can be induced in low CD3, CD4+, CD8+ (double positive) cells following activation with ConA and PMA/ionomycin (Martorell, J. et al. (1990) J. Immunol. 145:1356-1363). In contrast, in murine systems CD27 is constitutively expressed on all thymocytes (Gravestein, L. A. et al. (1994) Int. J. Immunol. 7:551-557). A soluble form of CD27 (the extracellular region clipped by a protease) appears in the culture supernatant and can also be detected in the serum of normal individuals (Hintzen, R. Q. et al. (1991) J. Neuroimmunol. 35:211-218). CD27 is also highly expressed in most of the B cell non-Hodgkin's lymphomas and B cell chronic lymphocytic leukemias (Ranheim, E. A. et al. (1995) Blood 85:3556-3565; Van Oers, M. H. et al. (1993) Blood 82:3430-3436). The B cell lines, Ramos and Raji, express significant levels of both CD27 and its ligand CD70.
Ligation of CD27 along with treatment of T cells with sub-optimal dose of PMA, PHA, anti-CD2 or anti-CD3 antibodies results in the proliferation of T cells, thus defining a costimulatory role for CD27. The CD27-mediated costimulatory effect can be specifically inhibited by the addition of anti-CD27 antibody, or recombinant sCD27 or anti-CD70 antibody (Sugita, K. et al. (1992) J. Immunol. 149:3208-3216; Hintzen, R. Q. et al. (1993) J. Immunol. 151:2426-2435; Hintzen, R. Q. et al. (1995) J. Immunol. 154:2612-2623, Kobata, T. et al. (1994) J. Immunol. 153:5422-5432). CD27/CD70 interaction can also result in the generation of cytolytic T cells (Goodwin, R. G. et al. (1993) Cell 73:447-456). Ligation of CD27 with CD70 on B cells significantly enhances IgG production, with a less pronounced effect on cell proliferation (Kobata, T. et al. (1995) PNAS 92:11249-11253). These studies clearly emphasize the importance of CD27/CD70 binding in both T-T, T-B and B-B cell interactions. Unlike CD28, CD27-mediated T cell proliferation does not support secretion of large amounts of IL2, clearly defining a different role for CD27/CD70 coupled co-stimulatory pathways. The CD45RA.sup.+ T cells which express CD27 are poor producers of IL2 and IL4 (Sugita, K. et al. (1992) J. Immunol. 151:2426-2435), as opposed to CD28 where coligation with TcR/CD3 complex results in elevated levels of IL2.
Thus, as CD27/CD70 binding is important in both T-T, T-B, and B-B cell interactions, it would be desirable to further elucidate the role of CD27 in T and B cell signaling.